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Open Access Research article

Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation

Yu Ohki1, Naoaki Shimada2, Aya Tominaga1, Satoko Osawa1, Takuya Higo2, Satoshi Yokoshima23, Tohru Fukuyama23, Taisuke Tomita14* and Takeshi Iwatsubo145

Author Affiliations

1 Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

2 Department of Synthetic Natural Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

3 Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan

4 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan

5 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

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Molecular Neurodegeneration 2014, 9:7  doi:10.1186/1750-1326-9-7

Published: 13 January 2014

Abstract

Background

Amyloid-β peptide ending at 42nd residue (Aβ42) is believed as a pathogenic peptide for Alzheimer disease. Although γ-secretase is a responsible protease to generate Aβ through a processive cleavage, the proteolytic mechanism of γ-secretase at molecular level is poorly understood.

Results

We found that the transmembrane domain (TMD) 1 of presenilin (PS) 1, a catalytic subunit for the γ-secretase, as a key modulatory domain for Aβ42 production. Aβ42-lowering and -raising γ-secretase modulators (GSMs) directly targeted TMD1 of PS1 and affected its structure. A point mutation in TMD1 caused an aberrant secretion of longer Aβ species including Aβ45 that are the precursor of Aβ42. We further found that the helical surface of TMD1 is involved in the binding of Aβ45/48 and that the binding was altered by GSMs as well as TMD1 mutation.

Conclusions

Binding between PS1 TMD1 and longer Aβ is critical for Aβ42 production.

Keywords:
Presenilin; Secretases; Alzheimer disease; Intramembrane proteolysis; γ-Secretase modulator